My laboratory has pioneered new research directions in environmental carcinogenesis for the past 25 years. We identified new targets for chemical carcinogens, new functions for ?old? tumor suppressor genes, and elucidated the first mechanism by which environmental exposures during development could reprogram the epigenome to increase cancer risk in adulthood. It is my goal to continue to advance the field of cancer research by tackling challenging questions, rather than performing incremental research, which while safe, does little to ?move the needle?. My objective for obtaining this R35 Outstanding Investigator Award is to focus my efforts on an exciting new discovery, which represents a paradigm shift in how we look at chromatin remodeler defects in cancer. As an unexpected off-shoot of our research on how environmental carcinogens reprogram the epigenome, we discovered a new function for the cell?s epigenetic machinery, and a new way for defects in chromatin remodeler genes to drive cancer. The Overarching Hypothesis for this R35 application is that the coding machinery known for ?reading, writing and erasing? epigenetic methyl marks on chromatin plays a second, equally important but heretofore unappreciated, coding function ?reading, writing and erasing? methyl marks on the cytoskeleton. We reported (Park et al Cell 2016), and support with additional Preliminary Data, that many chromatin remodelers are actually dual-function proteins, participating in both the Histone Code of chromatin, and the Tubulin Code of microtubules. This insight sets the stage for a new paradigm, wherein the cell?s methylation machinery serves two coding functions, one on chromatin and one on the cytoskeleton. It opens new frontiers for understanding how cells utilize and regulate one machinery with two distinct, but equally important coding functions. This is of special importance for cancer research, as we have been blind to the fact that defects in chromatin remodeler genes can directly impact the cytoskeleton, for example, via mitotic spindle defects that drive genomic instability and cytoskeletal defects that alter mobility to promote metastasis. The experiments proposed in this application are designed to open new doors for understanding the impact of chromatin remodeler defects in cancer, and for the development of therapies with efficacy against both the epigenetic and cytoskeletal alterations caused by defects in genes that encode dual-function chromatin-cytoskeleton remodelers.